The long-term goals of this project are to characterize the influence of antiretroviral therapies on myocardial energy homeostasis and to elucidate how these changes in substrate delivery adversely affect cardiac function in the stressed heart. The studies in this proposal are intended to establish direct effects of HIV protease inhibitors (PIs) on heart function in the setting of concomitant myocardial stress or injury, to identify the molecular mechanism(s) that are responsible for these changes, and to provide effective therapeutic strategies to prevent or ameliorate cardiac dysfunction. We hypothesize that drug-induced alterations in normal substrate delivery and/or utilization in the setting of acute and chronic stress impair contractile function, resulting in increased morbidity and mortality. We further hypothesize that the ability to increase myocardial glucose uptake will improve cardiac function and survival. To test these hypotheses, the effects of PIs on cardiac function and survival will be tested in murine models of dilated cardiomyopathy and myocardial infarction. The ability of PIs to affect nutrient sensing, alter insulin signaling, impair glucose uptake, and change myocardial calcium flux will be investigated both in vitro and in an isolated working heart model system. Finally, the ability of the incretin mimetic exenatide to improve insulin sensitivity and prolong survival in PI-treated mice will be tested. Taken together, these studies will provide new insights regarding the direct contribution of antiretroviral therapy to cardiac-related morbidity and mortality and will provide a rationale basis for efforts to improve the quality of life of HIV infected individuals at increased risk for the development of cardiovascular disease. PUBLIC HEALTH RELEVANCE: The medications used in the treatment of HIV-infected patients are known to contribute to the development of insulin resistance and diabetes, together with other changes that greatly increase the risk of heart disease. While the ability of these drugs to directly alter heart function has not been previously studied, recent clinical trials have shown an unexpected increase in adverse heart-related events in patients who have had intermittent treatment interruptions in an attempt to reduce treatment-related complications. Since HIV infection has transitioned from a fatal to a chronic disease, the health care costs for treating this aging population are predicted to increase dramatically in the coming decades. This research will generate a greater understanding of the direct effects of HIV therapies on insulin resistance in the heart and will provide rationale strategies to prevent and/or treat heart abnormalities in HIV. This research also has significant potential to improve the prevention and treatment of heart disease in the wider context of type 2 diabetes.